This invention relates to a method of preventing or treating cartilage damage by administering a gamma-aminobutyric acid (GABA)analog.
Cartilage damage is a major problem that afflicts many people worldwide. Many people engaged in athletic activities suffer from sprains and torn cartilage resulting from the physical activity. Cartilage damage is particularly prevalent within the aging population, as it generally is associated with degenerative diseases such as osteoarthritis.
Osteoarthritis (OA) is primarily a disorder of cartilage and subchondral bone, although other tissues in and around affected joints are involved. OA is a result of a complex system of interrelated mechanical, biochemical, and molecular mechanisms. OA is itself noninflammatory, although the cartilage damage that accompanies OA can initiate an inflammatory process secondary to OA. Many mechanisms can initiate the cellular and tissue events that constitute a final common pathway for osteoarthritis, including: congenital joint abnormalities; genetic defects (primary generalized OA); infectious, metabolic, endocrine, and neuropathic diseases; virtually any disease process that alters the normal structure and function of hyaline cartilage (e.g., RA, gout, chondrocalcinosis); and acute or chronic trauma (including fracture) to the hyaline cartilage or tissue surrounding it (e.g., prolonged overuse of a joint or group of joints, as in certain occupationsxe2x80x94foundry work, coal mining, and bus driving).
Treatment includes rehabilitation, patient education, drug therapy, and surgery when all conservative treatment has failed. Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) are the primary agents used to treat OA-related pain. These agents inhibit prostaglandin release by blocking cyclooxygenase-mediated conversion of cell membrane lipids from arachidonic acid. Muscle relaxants used to treat OA include diazepam, cyclobenzaprine, carisoprodol, and methocarbamol (usually in low doses). Analgesic drugs occasionally may be useful. Tricyclic antidepressants may be helpful for depressed patients. Each of these drugs only treat secondary conditions associated with cartilage damage such as inflammation, muscle tension, pain, or depression, but do not prevent or treat the primary condition, which is damage to the cartilage.
PCT International Application Publication No. WO 98/58641 describes a method of preventing and treating inflammatory diseases comprising administering to a subject suffering from such disease or suspected of developing such disease and in need of treatment an effective amount of a GABA analog. A preferred embodiment utilizes a cyclic amino acid compound of Formula I: 
wherein R1 is hydrogen or lower alkyl and n is an integer of from 4 to 6, and the pharmaceutically acceptable salts thereof. Another preferred embodiment utilizes a GABA analog of Formula II: 
or a pharmaceutically acceptable salt thereof, wherein:
R1 is straight or branched alkyl of from 1 to 6 carbon atoms, phenyl, or cycloalkyl of from 3 to 6 carbon atoms;
R2 is hydrogen or methyl; and
R3 is hydrogen, methyl, or carboxyl.
U.S. Pat. No. 6,001,876 describes a method of treating pain, especially for treatment of chronic pain disorders, using a compound of Formula II above.
PCT International Application Publication No. WO 99/37296 describes a method of treating muscular and skeletal pain comprising administering to a subject suffering from such pain an effective amount of a GABA analog, especially a compound of Formula I or II above.
However, applicant""s remarkable discoveryxe2x80x94disclosed in the instant applicationxe2x80x94that GABA analogs having the characteristic of being inhibitors of cartilage damage, or a pharmaceutically acceptable salt thereof, are useful for preventing or treating cartilage damage is not found or suggested in WO 98/58641, U.S. Pat. No. 6,001,876, or WO 99/37296.
Because many agents used to prevent or treat diseases with a component of cartilage damage actually treat secondary aspects such as inflammation or pain, but do not prevent or treat the damage to cartilage that underlies the diseases, the need for new therapies continues. We have now discovered the surprising result that a GABA analog having the characteristic of being an inhibitor of cartilage damage, or a pharmaceutically acceptable salt thereof, are useful to prevent or treat cartilage damage. All that is required to prevent and/or treat the cartilage damage according to the invention is to administer to a subject in need of treatment a cartilage damage preventing and/or treating amount of a GABA analog having the characteristic of being an inhibitor of cartilage damage, or a pharmaceutically acceptable salt thereof. None of the above references teach the instant method of preventing and/or treating cartilage damage.
Several GABA analogs are known. Gabapentin, a cyclic GABA analog, is now commercially available (Neurontin(copyright), Warner-Lambert Company) and extensively used clinically for treatment of epilepsy and neuropathic pain. Such cyclic GABA analogs are described in U.S. Pat. No. 4,024,175 and its divisional U.S. Pat. No. 4,087,544. Another series of GABA analogs is described in U.S. Pat. No. 5,563,175.
This invention provides a method of preventing or treating cartilage damage in a mammal suffering therefrom, comprising administering a therapeutically effective amount of a GABA analog having the characteristic of being an inhibitor of cartilage damage, or a pharmaceutically acceptable salt thereof.
A preferred embodiment of the invention method utilizes a GABA analog that is a cyclic amino acid compound of Formula I: 
wherein R1 is hydrogen or lower alkyl and n is an integer of from 4 to 6, and the pharmaceutically acceptable salts thereof. An especially preferred embodiment utilizes a compound of Formula I where R1 is hydrogen and n is 5, which compound is 1-(aminomethyl)-cyclohexane acetic acid, known generically as gabapentin. Other preferred GABA analogs, or a pharmaceutically acceptable salt thereof, are compounds of Formula I wherein the cyclic ring is substituted, for example with alkyl such as methyl or ethyl. Typical of such compounds include (1-aminomethyl-3-methylcyclohexyl) acetic acid, (1-aminomethyl-3-methylcyclopentyl) acetic acid, and (1-aminomethyl-3,4-dimethylcyclopentyl) acetic acid.
In another preferred embodiment, the invention method utilizes a GABA analog of Formula II: 
or a pharmaceutically acceptable salt thereof, wherein:
R1 is a straight or branched unsubstituted alkyl of from 1 to 6 carbon atoms, unsubstituted phenyl, or unsubstituted cycloalkyl of from 3 to 6 carbon atoms;
R2 is hydrogen or methyl; and
R3 is hydrogen, methyl, or carboxyl.
Diastereomers and enantiomers of compounds of Formula II can be utilized in the invention method.
An especially preferred embodiment of the invention method employs a compound of Formula II where R2 and R3 are both hydrogen, and R1 is xe2x80x94(CH2)0-2xe2x88x92i C4H9 as an (R), (S), or (R,S) isomer.
A more preferred embodiment of the invention method utilizes a compound of Formula II named 3-aminomethyl-5-methyl-hexanoic acid, or especially (S)-3-(aminomethyl)-5-methylhexanoic acid, now known generically as pregabalin. Pregabalin is also known as xe2x80x9cCI-1008xe2x80x9d and xe2x80x9cS-(+)-3-IBG.xe2x80x9d
Another preferred embodiment of the invention method utilizes a compound of Formula II named 3-(1-aminoethyl)-5-methylheptanoic acid or 3-(1-aminoethyl)-5-methylhexanoic acid.
Another preferred embodiment of the invention method utilizes a GABA analog that is a compound of Formulas III, IIIC, IIIF, IIIG, or IIIH: 
or a pharmaceutically acceptable salt thereof wherein:
n is an integer of from 0 to 2;
m is an integer of from 0 to 3;
R is sulfonamide,
amide,
phosphonic acid,
heterocycle,
sulfonic acid, or
hydroxamic acid;
Axe2x80x2 is a bridged ring selected from: 
xe2x80x83wherein 
xe2x80x83is the point of attachment;
Z1 to Z4 are each independently selected from hydrogen and methyl;
o is an integer of from 1 to 4; and
p is an integer of from 0 to 2.
In Formula 1 above R cannot be sulfonic acid when m is 2 and n is 1. (Suman-Chaulan N., et al., European Journal of pharmacology 1993;244:293-301.)
Another preferred embodiment of the invention method utilizes a compound of Formulas III, IIIC, IIIF, IIIG, or IIIH selected from:
(1-Aminomethyl-cyclohexylmethyl)-phosphonic acid;
(1R-trans)(1-Aminomethyl-3-methyl-cyclohexylmethyl)-phosphonic acid;
(trans)(1-Aminomethyl-3,4-dimethyl-cyclopentyhnethyl)-phosphonic acid;
(1R-trans)(1-Aminomethyl-3-methyl-cyclopentylmethyl)-phosphonic acid;
(1S-cis)(1-Aminomethyl-3-methyl-cyclopentylmethyl)-phosphonic acid;
(1S-trans)(1-Aminomethyl-3-methyl-cyclopentylmethyl)-phosphonic acid;
(1R-cis)(1-Aminomethyl-3-methyl-cyclopentylmethyl)-phosphonic acid;
(1xcex1,3xcex1,4xcex1)(1-Aminomethyl-3,4-dimethyl-cyclopentylmethyl)-phosphonic acid;
(1xcex1,3xcex2,4xcex2)(1-Aminomethyl-3,4-dimethyl-cyclopentylmethyl)-phosphonic acid;
(R)(1-Aminomethyl-3,3-dimethyl-cyclopentylmethyl)-phosphonic acid;
(S)(1-Aminomethyl-3,3-dimethyl-cyclopentylmethyl)-phosphonic acid;
(1-Aminomethyl-3,3-dimethyl-cyclobutylmethyl)-phosphonic acid;
2-(1-Aminomethyl-cyclohexyl)-N-hydroxy-acetamide;
(1S-trans)2-(1-Aminomethyl-3-methyl-cyclohexyl)-N-hydroxy-acetamide;
(trans)2-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-N-hydroxy-acetamide;
(1S-cis)2-(1-Aminomethyl-3-methyl-cyclopentyl)-N-hydroxy-acetamide;
(1R-trans)2-(1-Aminomethyl-3-methyl-cyclopentyl)-N-hydroxy-acetamide;
(1R-cis)2-(1-Aminomethyl-3-methyl-cyclopentyl)-N-hydroxy-acetamide;
(1S-trans)2-(1-Aminomethyl-3-methyl-cyclopentyl)-N-hydroxy-acetamide;
(1xcex1,3xcex1,4xcex1)2-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-N-hydroxy-acetamide;
(1xcex1,3xcex2,4xcex2)2-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-N-hydroxy-acetamide;
(S)2-(1-Aminomethyl-3,3dimethyl-cyclopentyl)-N-hydroxy-acetamide;
(R)2-(1-Aminomethyl-3,3-dimethyl-cyclopentyl)-N-hydroxy-acetamide;
2-(1-Aminomethyl-3,3-dimethyl-cyclobutyl)-N-hydroxy-acetamide;
N-[2-(1-Aminomethyl-cyclohexyl)-ethyl]-methanesulfonamide;
(1S-cis)N-[2-(1-Aminomethyl-3-methyl-cyclohexyl)-ethyl]-methanesulfonamide;
(trans)N-[2-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-ethyl]-methanesulfonamide;
(1S-cis)N-[2-(1-Aminomethyl-3-methyl-cyclopentyl)-ethyl]-methanesulfonamide;
(1R-trans)N-[2-(1-Aminomethyl-3-methyl-cyclopentyl)-ethyl]-methanesulfonamide;
(1R-cis)N-[2-(1-Aminomethyl-3-methyl-cyclopentyl)-ethyl]-methanesulfonamide;
(1S-cis)N-[2-(1-Aminomethyl-3-methyl-cyclopentyl)-ethyl]-methanesulfonamide;
(1xcex1,3xcex1,4xcex1)N-[2-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-ethyl]-methanesulfonamide;
(1xcex1,3xcex2,4xcex2)N-[2-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-ethyl]-methanesulfonamide;
(S)N-[2-(1-Aminomethyl-3,3-dimethyl-cyclopentyl)-ethyl]-methanesulfonamide;
(R)N-[2-(1-Aminomethyl-3,3-dimethyl-cyclopentyl)-ethyl]-methanesulfonamide;
N-[2-(1-Aminomethyl-3,3-dimethyl-cyclobutyl)-ethyl]-methanesulfonamide;
(1S-cis)3-(1-Aminomethyl-3-methyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one;
(trans)3-(1-Aminomethyl-3,4-dimethyl-cyclopentylmethyl)-4H-[1,2,4]oxadiazol-5-one;
(1S-cis)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl)-4H-[1,2,4]oxadiazol-5-one;
(1R-trans)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl)-4H-[1,2,4]oxadiazol-5-one;
(1R-cis)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl)-4H-[1,2,4]oxadiazol-5-one;
(1S-trans)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl)-4H-[1,2,4]oxadiazol-5-one;
(1xcex1,3xcex1,4xcex1)3-(1-Aminomethyl-3,4-dimethyl-cyclopentylmethyl)-4H-[1,2,4]oxadiazol-5-one;
(1xcex1,3xcex2,4xcex2)3-(1-Aminomethyl-3,4-dimethyl-cyclopentylmethyl)-4H-[1,2,4]oxadiazol-5-one;
(S)3-(1-Aminomethyl-3,3-dimethyl-cyclopentylmethyl)-4H-[1,2,4]oxadiazol-5-one;
(R)3-(1-Aminomethyl-3,3-dimethyl-cyclopentylmethyl)-4H-[1,2,4]oxadiazol-5-one;
3-(1-Aminomethyl-3,3-dimethyl-cyclobutylmethyl)-4H-[1,2,4]oxadiazol-5-one;
3-(1-Aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazole-5-thione;
(1S-cis)3-(1-Aminomethyl-3-methyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazole-5-thione;
(trans)3-(1-Aminomethyl-3,4-dimethyl-cyclopentylmethyl)-4H-[1,2,4]oxadiazole-5-thione;
(1S-cis)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl)-4H-[1,2,4]oxadiazole-5-thione;
(1R-trans)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl)-4H-[1,2,4]oxadiazole-5-thione;
(1R-cis)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl)-4H-[1,2,4]oxadiazole-5-thione;
(1S-trans)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl)-4H-[1,2,4]oxadiazole-5-thione;
(1xcex1,3xcex1,4xcex1)3-(1-Aminomethyl-3,4-dimethyl-cyclopentylmethyl)-4H-[1,2,4]oxadiazole-5-thione;
(1xcex1,3xcex2,40xcex2)3-(1-Aminomethyl-3,4-dimethyl-cyclopentylmethyl)-4H-[1,2,4]oxadiazole-5-thione;
(S)3-(1-Aminomethyl-3,3-dimethyl-cyclopentylmethyl)-4H-[1,2,4]oxadiazole-5-thione;
(R)3-(1-Aminomethyl-3,3-dimethyl-cyclopentylmethyl)-4H-[1,2,4]oxadiazole-5-thione;
3-(1-Aminomethyl-3,3-dimethyl-cyclobutylmethyl)-4H-[1,2,4]oxadiazole-5-thione;
C-[1-(1H-Tetrazol-5-ylmethyl)-cyclohexyl]-methylamine;
(1S-cis)C-[3-Methyl-1-(1H-tetrazol-5-ylmethyl)-cyclohexyl]-methylamine;
(trans)C-[3,4-Dimethyl-1-(1H-tetrazol-5-ylmethyl)-cyclopentyl]-methylamine;
(1S-cis)C-[3-Methyl-1-(1H-tetrazol-5-ylmethyl)-cyclopentyl]-methylamine;
(1R-trans)C-[3-Methyl-1-(1H-tetrazol-5-ylmethyl)-cyclopentyl]-methylamine;
(1R-cis)C-[3-Methyl-1-(1H-tetrazol-5-ylmethyl)-cyclopentyl]-methylamine;
(1S-trans)C-[3-Methyl-1-(1H-tetrazol-5-ylmethyl)-cyclopentyl]-methylamine;
(1xcex1,3xcex1,4xcex1)C-[3,4-Dimethyl-1-(1H-tetrazol-5-ylmethyl)-cyclopentyl]-methylamine;
(1xcex1,3xcex2,4xcex2)C-[3,4-Dimethyl-1-(1H-tetrazol-5-ylmethyl)-cyclopentyl]-methylamine;
(S)C-[3,3-Dimethyl-1-(1H-tetrazol-5-ylmethyl)-cyclopentyl]-methylamine;
(R)C-[3,3-Dimethyl-1-(1H-tetrazol-5-ylmethyl)-cyclopentyl]-methylamine;
C-[3,3-Dimethyl-1-(1H-tetrazol-5-ylmethyl)-cyclobutyl]-methylamine;
N-[2-(1-Aminomethyl-cyclohexyl)-ethyl]-C,C,C-trifluoro-methanesulfonamide;
(1S-cis)N-[2-(1-Aminomethyl-3-methyl-cyclohexyl)-ethyl]-C,C,C-trifluoro-methanesulfonamide;
(trans)N-[2-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-ethyl]-C,C,C-trifluoro-methanesulfonamide;
(1R-cis)N-[2-(1-Aminomethyl-3-methyl-cyclopentyl)-ethyl]-C,C,C-trifluoro-methanesulfonamide;
(1S-trans)N-[2-(1-Aminomethyl-3-methyl-cyclopentyl)-ethyl]-C,C,C-trifluoro-methanesulfonamide;
(1S-cis)N-[2-(1-Aminomethyl-3-methyl-cyclopentyl)-ethyl]-C,C,C-trifluoro-methanesulfonamide;
(1R-trans)N-[2-(1-Aminomethyl-3-methyl-cyclopentyl)-ethyl]-C,C,C-trifluoro-methanesulfonamide;
(1xcex1,3xcex1,4xcex1)N-[2-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-ethyl]-C,C,C-trifluoro-methanesulfonamide;
(1xcex1,3xcex2,4xcex2)N-[2-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-ethyl]-C,C,C-trifluoro-methanesulfonamide;
(S)N-[2-(1-Aminomethyl-3,3-dimethyl-cyclopentyl)-ethyl]-C,C,C-trifluoro-methanesulfonamide;
(R)N-[2-(1-Aminomethyl-3,3-dimethyl-cyclopentyl)-ethyl]-C,C,C-trifluoro-methanesulfonamide;
N-[2-(1-Aminomethyl-3,3-dimethyl-cyclobutyl)-ethyl]-C,C,C-trifluoro-methanesulfonamide;
3-(1-Aminomethyl-cyclohexylmethyl)-4H-[1,2,4]thiadiazol-5-one;
(1S-cis)3-(1-Aminomethyl-3-methyl-cyclohexylmethyl)-4H-[1,2,4]thiadiazol-5-one;
(trans)3-(1-Aminomethyl-3,4-dimethyl-cyclopentylmethyl)-4H-[1,2,4]thiadiazol-5-one;
(1R-cis)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl)-4H-[1,2,4]thiadiazol-5-one;
(1S-trans)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl)-4H-[1,2,4]thiadiazol-5-one;
(1S-cis)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl)-4H-[1,2,4]thiadiazol-5-one;
(1R-trans)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl)-4H-[1,2,4]thiadiazol-5-one;
(1xcex1,3xcex1,4xcex1)3-(1-Aminomethyl-3,4-dimethyl-cyclopentylmethyl)-4H-[1,2,4]thiadiazol-5-one;
(1xcex1,3xcex2,4xcex2)3-(1-Aminomethyl-3,4-dimethyl-cyclopentylmethyl)-4H-[1,2,4]thiadiazol-5-one;
(S)3-(1-Aminomethyl-3,3-dimethyl-cyclopentylmethyl)-4H-[1,2,4]thiadiazol-5-one;
(R)3-(1-Aminomethyl-3,3-dimethyl-cyclopentylmethyl)-4H-[1,2,4]thiadiazol-5-one;
3-(1-Aminomethyl-3,3-dimethyl-cyclobutylmethyl)-4H-[1,2,4]thiadiazol-5-one;
C-[1-(2-Oxo-2,3-dihydro-2xcex4-[1,2,3,5]oxathiadiazol-4-ylmethyl)-cyclohexyl]-methylamine;
(1S-cis)C-[3-Methyl-1-(2-oxo-2,3-dihydro-2xcex4-[1,2,3,5]oxathiadiazol-4-ylmethyl)-cyclohexyl]-methylamine;
(trans)C-[3,4-Dimethyl-1-(2-oxo-2,3-dihydro-2xcex4-[1,2,3,5]oxathiadiazol-4-ylmethyl)-cyclopentyl]-methylamine;
(1S-cis)C-[3-Methyl-1-(2-oxo-2,3-dihydro-2xcex4-[1,2,3,5]oxathiadiazol-4-ylmethyl)-cyclopentyl]-methylamine;
(1R-trans)C-[3-Methyl-1-(2-oxo-2,3-dihydro-2xcex4-[1,2,3,5]oxathiadiazol-4-ylmethyl)-cyclopentyl]-methylamine;
(1R-cis)C-[3-Methyl-1-(2-oxo-2,3-dihydro-2xcex4-[1,2,3,5]oxathiadiazol-4-ylmethyl)-cyclopentyl]-methylamine;
(1S-trans)C-[3-Methyl-1-(2-oxo-2,3-dihydro-2xcex4-[1,2,3,5]oxathiadiazol-4-ylmethyl)-cyclopentyl]-methylamine;
(1xcex1,3xcex1,4xcex1)C-[3,4-Dimethyl-1-(2-oxo-2,3-dihydro-2xcex4-[1,2,3,5]oxathiadiazol-4-ylmethyl)-cyclopentyl]-methylamine;
(1xcex1,3xcex2,4xcex2)C-[3,4-Dimethyl-1-(2-oxo-2,3-dihydro-2xcex4-[1,2,3,5]oxathiadiazol-4-ylmethyl)-cyclopentyl]-methylamine;
(S)C-[3,3-Dimethyl-1-(2-oxo-2,3-dihydro-2xcex4-[1,2,3,5]oxathiadiazol-4-ylmethyl)-cyclopentyl]-methylamine;
(R)C-[3,3-Dimethyl-1-(2-oxo-2,3-dihydro-2xcex4-[1,2,3,5]oxathiadiazol-4-ylmethyl)-cyclopentyl]-methylamine;
C-[3,3-Dimethyl-1-(2-oxo-2,3-dihydro-2xcex4-[1,2,3,5]oxathiadiazol-4-ylmethyl)-cyclobutyl]-methylamine;
(1-Aminomethyl-cyclohexyl)-methanesulfonamide;
(1R-trans)(1-Aminomethyl-3-methyl-cyclohexyl)-methanesulfonamide;
(trans)(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-methanesulfonamide;
(1S-trans)(1-Aminomethyl-3-methyl-cyclopentyl)-methanesulfonamide;
(1R-cis)(1-Aminomethyl-3-methyl-cyclopentyl)-methanesulfonamide;
(1R-trans)(1Aminomethyl-3-methyl-cyclopentyl)-methanesulfonamide;
(1S-cis)(1-Aminomethyl-3-methyl-cyclopentyl)-methanesulfonamide;
(1xcex1,3xcex2,4xcex2)(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-methanesulfonamide;
(1xcex1,3xcex1,4xcex1)(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-methanesulfonamide;
(R)(1-Aminomethyl-3,3-dimethyl-cyclopentyl)-methanesulfonamide;
(S)(1-Aminomethyl-3,3-dimethyl-cyclopentyl)-methanesulfonamide;
(1-Aminomethyl-3,3-dimethyl-cyclobutyl)-methanesulfonamide;
(1-Aminomethyl-cyclohexyl)-methanesulfonic acid;
(1R-trans) (1-Aminomethyl-3methyl-cyclohexyl)-methanesulfonic acid;
(trans)(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-methanesulfonic acid;
(1S-trans)(1-Aminomethyl-3-methyl-cyclopentyl)-methanesulfonic acid;
(1S-cis)(1-Aminomethyl-3-methyl-cyclopentyl)-methanesulfonic acid;
(1R-trans)(1-Aminomethyl-3-methyl-cyclopentyl)-methanesulfonamide acid;
(1R-cis)(1-Aminomethyl-3-methyl-cyclopentyl)-methanesulfonic acid;
(1xcex1,3xcex2,4xcex2)(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-methanesulfonic acid;
(1xcex1,3xcex1,4xcex1)(1-Aminomethyl -3,4-diethyl-cyclopentyl)-methanesulfonic acid;
(R)(1-Aminomethyl-3,3-dimethyl-cyclopentyl)-methanesulfonic acid;
(S)(1-Aminomethyl-3,3-dimethyl-cyclopentyl)-methanesulfonic acid;
(1-Aminomethyl-3,3-dimethyl-cyclobutyl)-methanesulfonic acid;
(1-Aminomethyl-cyclopentylmethyl)-phosphonic acid;
2-(1-Aminomethyl-cyclopentyl)-N-hydroxy-acetamide;
N-[2-(1-Aminomethyl-cyclopentyl)-ethyl]-methanesulfonamide;
3-(1-Aminomethyl-cyclopentylmethyl)-4H-[1,2,4]oxadiazol-5-one;
3-(1-Aminomethyl-cyclopentylmethyl)-4H-[1,2,4]oxadiazole-5-thione;
C-[1-(1H-Tetrazol-5-ylmethyl)-cyclopentyl]-methylamine;
N-[2-(1-Aminomethyl-cyclopentyl)-ethyl]-C,C,C-trifluoro-methanesulfonamide;
3-(1-Aminomethyl-cyclopentylmethyl)-4H-[1,2,4]thiadiazol-5-one;
C-[1-(2-Oxo-2,3-dihydro-2xcex4-[1,2,3,5]oxathiadiazol-4-ylmethyl)-cyclopentyl]-methylamine;
(1-Aminomethyl-cyclopentyl)-methanesulfonamide;
(1-Aminomethyl-cyclopentyl)-methanesulfonic acid;
(9-Aminomethyl-bicyclo[3.3.1]non-9-ylmethyl)-phosphonic acid;
2-(9-Aminomethyl-bicyclo[3.3.1 ]non-9-yl)-N-hydroxy-acetamide;
N-[2-(9-Aminomethyl-bicyclo[3.3.1]non-9-yl)-ethyl]-methanesulfonamide;
3-(9-Aminomethyl-bicyclo[3.3.1]non-9-ylmethyl)-4H-[1,2,4]oxadiazol-5-one;
3-(9-Aminomethyl-bicyclo[3.3.1]non-9-ylmethyl)-4H-[1,2,4]oxadiazole-5-thione;
C-[9-(1H-Tetrazol-5-ylmethyl)-bicyclo[3.3.1]non-9-yl]-methylamine;
N-[2-(9-Aminomethyl-bicyclo[3.3.1]non-9-yl)-ethyl]-C,C,C-trifluoro-methanesulfonamide;
3-(9-Aminomethyl-bicyclo[3.3.1 ]non-9-ylmethyl)-4H-[1,2,4]thiadiazol-5-one;
C-[9-(2-Oxo-2,3-dihydro-2xcex4-[1,2,3,5]oxathiadiazol-4-ylmethyl)-bicyclo[3.3.1]non-9-yl]-methylamine;
(9-Aminomethyl-bicyclo[3.3.1]non-9-yl)-methanesulfonamide;
(9-Aminomethyl-bicyclo[3.3.1]non-9-yl)-methanesulfonic acid;
(2-Aminomethyl-adamantan-2-ylmethyl)-phosphonic acid;
2-(2-Aminomethyl-adamantan-2-yl)-N-hydroxy-acetamide;
N-[2-(2-Aminomethyl-adamantan-2-yl)-ethyl]-methanesulfonamide;
3-(2-Aminomethyl-adamantan-2-ylmethyl)-4H-[1,2,4]oxadiazol-5-one;
3-(2-Aminomethyl-adamantan-2-ylmethyl)-4H-[1,2,4]oxadiazole-5-thione;
C-[2-(1H-Tetrazol-5-ylmethyl)-adamantan-2-yl]-methylamine;
N-[2-(2-Aminomethyl-adamantan-2-yl)-ethyl]-C,C,C-trifluoromethanesulfonamide;
3-(2-Aminomethyl-adamantan-2-ylmethyl)-4H-[1,2,4]thiadiazol-5-one;
C-[2-(2-Oxo-2,3-dihydro-2xcex4-[1,2,3,5]oxathiadiazol-4-ylmethyl)-adamantan-2-yl]-methylamine;
(2-Aminomethyl-adamantan-2-yl)-methanesulfonamide;
(2-Aminomethyl-adamantan-2-yl)-methanesulfonic acid;
(1-Aminomethyl-cycloheptylmethyl)-phosphonic acid;
2-(1-Aminomethyl-cycloheptyl)-N-hydroxy-acetamide;
N-[2-(1-Aminomethyl-cycloheptyl)-ethyl]-methanesulfonamide;
3-(1-Aminomethyl-cycloheptylmethyl)-4H-[1,2,4]oxadiazole-5-thione;
N-[2-(1-Aminomethyl-cycloheptyl)-ethyl]-C,C,C-trifluoromethanesulfonamide;
C-[1-(2-Oxo-2,3-dihydro-2 14-[1,2,3,5]oxathiadiazol-4-ylmethyl)-cycloheptyl]-methylamine;
(1-Aminomethyl-cycloheptyl)-methanesulfonamide; and
(1-Aminomethyl-cycloheptyl)-methanesulfonic acid.
Another preferred embodiment of the invention method utilizes a compound of Formulas III, IIIC, IIIF, IIIG, or IIIH, wherein preferred compounds are those wherein R is a sulfonamide selected from xe2x80x94NHSO2R15 or xe2x80x94SO2NHR15 wherein R15 is straight or branched alkyl or trifluoromethyl.
Another preferred embodiment of the invention method utilizes a compound of Formulas III, IIIC, IIIF, IIIG, or IIIH, wherein especially preferred is N-[2-(1-aminomethyl-cyclohexyl)-ethyl]-methanesulfonamide.
Another preferred embodiment of the invention method utilizes a compound of Formulas III, IIIC, IIIF, IIIG, or IIIH, wherein other preferred compounds are those wherein R is a phosphonic acid, xe2x80x94PO3H2.
Another preferred embodiment of the invention method utilizes a compound of Formulas III, IIIC, IIIF, IIIG, or IIIH, wherein especially preferred are (1-aminomethyl-cyclohexylmethyl)-phosphonic acid and (2-aminomethyl-4-methyl-pentyl)-phosphonic acid.
Another preferred embodiment of the invention method utilizes a compound of Formulas III, IIIC, IIIF, IIIG, or IIIH, wherein other preferred compounds are those wherein R is a heterocycle selected from: 
Another preferred embodiment of the invention method utilizes a compound of Formulas III, IIIC, IIIF, IIIG, or IIIH, wherein especially preferred are C-[1-(1H-tetrazol-5-ylmethyl)cyclohexyl]-methylamine and 4-methyl-2-(1H-tetrazol-5-ylmethyl)-pentylamine.
An especially preferred embodiment of the invention method utilizes a compound of Formula III wherein:
m is an integer of from 0 to 2;
p is an integer of 2; and: 
Still more preferred is an embodiment of the invention method which utilizes a compound of Formulas III, IIIC, IIIF, IIIG, or IIIH named 3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one, or a pharmaceutically acceptable salt thereof.
Still more preferred is an embodiment of the invention method which utilizes a compound of Formulas III, IIIC, IIIF, IIIG, or IIIH named 3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one hydrochloride.
Also preferred is an embodiment of the invention method which utilizes a compound of Formulas III, IIIC, IIIF, IIIG, or IIIH named 3-(1-aminomethyl-cycloheptylmethyl)-4H-[1,2,4]oxadiazol-5-one, or a pharmaceutically acceptable salt thereof.
Also more preferred is an embodiment of the invention method which utilizes a compound of Formulas III, IIIC, IIIF, IIIG, or IIIH named 3-(1-aminomethyl-cycloheptylmethyl)-4H-[1,2,4]oxadiazol-5-one hydrochloride.
Also preferred is an embodiment of the invention method which utilizes a compound of Formulas III, IIIC, IIIF, IIIG, or IIIH named C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, or a pharmaceutically acceptable salt thereof.
Also more preferred is an embodiment which utilizes a compound of Formulas III, IIIC, IIIF, IIIG, or IIIH named C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine.
Another preferred embodiment of the invention method utilizes a GABA analog that is a compound of Formula IV: 
or a pharmaceutically acceptable salt thereof wherein:
R1 is hydrogen, straight or branched alkyl of from 1 to 6 carbon atoms or phenyl;
R2 is straight or branched alkyl of from 1 to 8 carbon atoms,
straight or branched alkenyl of from 2 to 8 carbon atoms,
cycloalkyl of from 3 to 7 carbon atoms,
alkoxy of from 1 to 6 carbon atoms,
-alkylcycloalkyl,
-alkylalkoxy,
-alkyl OH
-alkylphenyl,
-alkylphenoxy,
-phenyl or substituted phenyl; and
R1 is straight or branched alkyl of from 1 to 6 carbon atoms or phenyl when R2 is methyl.
Preferred is an embodiment of the invention method employing a compound of Formula IV wherein R1 is hydrogen, and R2 is alkyl.
Another preferred embodiment of the invention method employing a compound of Formula IV wherein R1 is methyl, and R2 is alkyl.
Still another preferred embodiment of the invention method utilizes a compound of Formula IV wherein R1 is methyl, and R2 is methyl or ethyl.
Especially preferred is an embodiment of the invention method utilizing a compound of Formula IV selected from:
3-Aminomethyl-5-methylheptanoic acid;
3-Aminomethyl-5-methyl-octanoic acid;
3-Aminomethyl-5-methyl-nonanoic acid;
3-Aminomethyl-5-methyl-decanoic acid;
3-Aminomethyl-5-methyl-undecanoic acid;
3-Aminomethyl-5-methyl-dodecanoic acid;
3-Aminomethyl-5-methyl-tridecanoic acid;
3-Aminomethyl-5-cyclopropyl-hexanoic acid;
3-Aminomethyl-5-cyclobutyl-hexanoic acid;
3-Aminomethyl-5-cyclopentyl-hexanoic acid;
3-Aminomethyl-5-cyclohexyl-hexanoic acid;
3-Aminomethyl-5-trifluoromethyl-hexanoic acid;
3-Aminomethyl-5-phenyl-hexanoic acid;
3-Aminomethyl-5-(2-chlorophenyl)-hexanoic acid;
3-Aminomethyl-5-(3-chlorophenyl)-hexanoic acid;
3-Aminomethyl-5-(4-chlorophenyl)-hexanoic acid;
3-Aminomethyl-5-(2-methoxyphenyl)-hexanoic acid;
3-Aminomethyl-5-(3-methoxyphenyl)-hexanoic acid;
3-Aminomethyl-5-(4-methoxyphenyl)-hexanoic acid; and
3-Aminomethyl-5-(phenylmethyl)-hexanoic acid.
Another especially preferred embodiment of the invention method uses a compound of Formula IV selected from:
(3R,4S)-3-Aminomethyl-4,5-dimethyl-hexanoic acid;
3-Aminomethyl-4,5-dimethyl-hexanoic acid;
(3R,4S)-3-Aminomethyl-4,5-dimethyl-hexanoic acid MP;
(3S,4S)-3-Aminomethyl-4,5-dimethyl-hexanoic acid;
(3R,4R)-3-Aminomethyl-4,5-dimethyl-hexanoic acid MP;
3-Aminomethyl-4-isopropyl-hexanoic acid;
3-Aminomethyl-4-isopropyl-heptanoic acid;
3-Aminomethyl-4-isopropyl-octanoic acid;
3-Aminomethyl-4-isopropyl-nonanoic acid;
3-Aminomethyl-4-isopropyl-decanoic acid; and
3-Aminomethyl-4-phenyl-5-methyl-hexanoic acid.
Another preferred embodiment of the invention method uses a compound of Formula IV selected from:
(3S,5S)-3-Aminomethyl-5-methoxy-hexanoic acid;
(3S,5S)-3-Aminomethyl-5-ethoxy-hexanoic acid;
(3S,5S)-3-Aminomethyl-5-propoxy-hexanoic acid;
(3S,5S)-3-Aminomethyl-5-isopropoxy-hexanoic acid;
(3S,5S)-3-Aminomethyl-5-tert-butoxy-hexanoic acid;
(3S,5S)-3-Aminomethyl-5-fluoromethoxy-hexanoic acid;
(3S,5S)-3-Aminomethyl-5-(2-fluoro-ethoxy)-hexanoic acid;
(3S,5S)-3-Aminomethyl-5-(3,3,3-trifluoro-propoxy)-hexanoic acid;
(3S,5S)-3-Aminomethyl-5-phenoxy-hexanoic acid;
(3S,5S)-3-Aminomethyl-5-(4-chloro-phenoxy)-hexanoic acid;
(3S,5S)-3-Aminomethyl-5-(3-chloro-phenoxy)-hexanoic acid;
(3S,5S)-3-Aminomethyl-5-(2-chloro-phenoxy)-hexanoic acid;
(3S,5S)-3-Aminomethyl-5-(4-fluoro-phenoxy)-hexanoic acid;
(3S,5S)-3-Aminomethyl-5-(3-fluoro-phenoxy)-hexanoic acid;
(3S,5S)-3-Aminomethyl-5-(2-fluoro-phenoxy)-hexanoic acid;
(3S,5S)-3-Aminomethyl-5-(4-methoxy-phenoxy)-hexanoic acid;
(3S,5S)-3-Aminomethyl-5-(3-methoxy-phenoxy)-hexanoic acid;
(3S,5S)-3-Aminomethyl-5-(2-methoxy-phenoxy)-hexanoic acid;
(3S,5S)-3-Aminomethyl-5-(4-nitro-phenoxy)-hexanoic acid;
(3S,5S)-3-Aminomethyl-5-(3-nitro-phenoxy)-hexanoic acid;
(3S,5S)-3-Aminomethyl-5-(2-nitro-phenoxy)-hexanoic acid;
(3S,5S)-3-Aminomethyl-6-hydroxy-5-methyl-hexanoic acid;
(3S,5S)-3-Aminomethyl-6-methoxy-5-methyl-hexanoic acid;
(3S,5S)-3-Aminomethyl-6-ethoxy-5-methyl-hexanoic acid;
(3S,5S)-3-Aminomethyl-5-methyl-6-propoxy-hexanoic acid;
(3S,5S)-3-Aminomethyl-6-isopropoxy-5-methyl-hexanoic acid;
(3S,5S)-3-Aminomethyl-6-tert-butoxy-5-methyl-hexanoic acid;
(3S,5S)-3-Aminomethyl-6-fluoromethoxy-5-methyl-hexanoic acid;
(3S,5S)-3-Aminomethyl-6-(2-fluoro-ethoxy)-5-methyl-hexanoic acid;
(3S,5S)-3-Aminomethyl-5-methyl-6-(3,3,3-trifluoro-propoxy)-hexanoic acid;
(3S,5S)-3-Aminomethyl-5-methyl-6-phenoxy-hexanoic acid;
(3S,5S)-3-Aminomethyl-6-(4-chloro-phenoxy)-5-methyl-hexanoic acid;
(3S,5S)-3-Aminomethyl-6-(3-chloro-phenoxy)-5-methyl-hexanoic acid;
(3S,5S)-3-Aminomethyl-6-(2-chloro-phenoxy)-5-methyl-hexanoic acid;
(3S,5S)-3-Aminomethyl-6-(4-fluoro-phenoxy)-5-methyl-hexanoic acid;
(3S,5S)-3-Aminomethyl-6-(3-fluoro-phenoxy)-5-methyl-hexanoic acid;
(3S,5S)-3-Aminomethyl-6-(2-fluoro-phenoxy)-5-methyl-hexanoic acid;
(3S,5S)-3-Aminomethyl-6-(4-methoxy-phenoxy)-5-methyl-hexanoic acid;
(3S,5S)-3-Aminomethyl-6-(3-methoxy-phenoxy)-5-methyl-hexanoic acid;
(3S,5S)-3-Aminomethyl-6-(2-methoxy-phenoxy)-5-methyl-hexanoic acid;
(3S,5S)-3-Aminomethyl-5-methyl 6-(4-trifluoro methyl-phenoxy)-hexanoic acid;
(3S,5S)-3-Aminomethyl-5-methyl 6-(3-trifluoromethyl-phenoxy)-hexanoic acid;
(3S,5S)-3-Aminomethyl-5-methyl 6-(2-trifluoromethyl-phenoxy)-hexanoic acid;
(3S,5S)-3-Aminomethyl-5-methyl 6-(4-nitro-phenoxy)-hexanoic acid;
(3S,5S)-3-Aminomethyl-5-methyl 6-(3-nitro-phenoxy)-hexanoic acid;
(3S,5S)-3-Aminomethyl-5-methyl 6-(2-nitro-phenoxy)-hexanoic acid;
(3S,5S)-3-Aminomethyl-6-benzyloxy-5-methyl- hexanoic acid;
(3S,5S)-3-Aminomethyl-7-hydroxy-5-methyl-heptanoic acid;
(3S,5S)-3-Aminomethyl-7-methoxy-5-methyl-heptanoic acid;
(3S,5S)-3-Aminomethyl-7-ethoxy-5-methyl-heptanoic acid;
(3S,5S)-3-Aminomethyl-5-methyl-7-propoxy-heptanoic acid;
(3S,5S)-3-Aminomethyl-7-isopropoxy-5-methyl-heptanoic acid;
(3S,5S)-3-Aminomethyl-7-tert-butoxy-5-methyl-heptanoic acid;
(3S,5S)-3-Aminomethyl-7-fluoromethoxy-5-methyl-heptanoic acid;
(3S,5S)-3-Aminomethyl-7-(2-fluoro-ethoxy)-5-methyl-heptanoic acid;
(3S,5S)-3-Aminomethyl-5-methyl-7-(3,3,3-trifluoro-propoxy)-heptanoic acid;
(3S,5S)-3-Aminomethyl-7-benzyloxy-5-methyl-heptanoic acid;
(3S,5S)-3-Aminomethyl-5-methyl-7-phenoxy-heptanoic acid;
(3S,5S)-3-Aminomethyl-7-(4-chloro-phenoxy)-5-methyl-heptanoic acid;
(3S,5S)-3-Aminomethyl-7-(3-chloro-phenoxy)-5-methyl-heptanoic acid;
(3S,5S)-3-Aminomethyl-7-(2-chloro-phenoxy)-5-methyl-heptanoic acid;
(3S,5S)-3-Aminomethyl-7-(4-fluoro-phenoxy)-5-methyl-heptanoic acid;
(3S,5S)-3-Aminomethyl-7-(3-fluoro-phenoxy)-5-methyl-heptanoic acid;
(3S,5S)-3-Aminomethyl-7-(2-fluoro-phenoxy)-5-methyl-heptanoic acid;
(3S,5S)-3-Aminomethyl-7-(4-methoxy-phenoxy)-5-methyl-heptanoic acid;
(3S,5S)-3-Aminomethyl-7-(3-methoxy-phenoxy)-5-methyl-heptanoic acid;
(3S,5S)-3-Aminomethyl-7-(2-methoxy-phenoxy)-5-methyl-heptanoic acid;
(3S,5S)-3-Aminomethyl-5-methyl-7-(4-trifluoromethyl-phenoxy)-heptanoic acid;
(3S,5S)-3-Aminomethyl-5-methyl-7-(3-trifluoromethyl-phenoxy)-heptanoic acid;
(3S,5S)-3-Aminomethyl-5-methyl-7-(2-trifluoromethyl-phenoxy)-heptanoic acid;
(3S,5S)-3-Aminomethyl-5-methyl-7-(4-nitro-phenoxy)-heptanoic acid;
(3S,5S)-3-Aminomethyl-5-methyl-7-(3-nitro-phenoxy)-heptanoic acid;
(3S,5S)-3-Aminomethyl-5-methyl-7-(2-nitro-phenoxy)-heptanoic acid;
(3S,5S)-3-Aminomethyl-5-methyl-6-phenyl-hexanoic acid;
(3S,5S)-3-Aminomethyl-6-(4-chloro-phenyl)-5-methyl-hexanoic acid;
(3S,5S)-3-Aminomethyl-6-(3-chloro-phenyl)-5-methyl-hexanoic acid;
(3S,5S)-3-Aminomethyl-6-(2-chloro-phenyl)-5-methyl-hexanoic acid;
(3S,5S)-3-Aminomethyl-6-(4-methoxy-phenyl)-5-methyl-hexanoic acid;
(3S,5S)-3-Aminomethyl-6-(3-methoxy-phenyl)-5-methyl-hexanoic acid;
(3S,5S)-3-Aminomethyl-6-(2-methoxy-phenyl)-5-methyl-hexanoic acid;
(3S,5S)-3-Aminomethyl-6-(4-fluoro-phenyl)-5-methyl-hexanoic acid;
(3S,5S)-3-Aminomethyl-6-(3-fluoro-phenyl)-5-methyl-hexanoic acid;
(3S,5S)-3-Aminomethyl-6-(2-fluoro-phenyl)-5-methyl-hexanoic acid;
(3S,5R)-3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid;
(3S,5R)-3-Aminomethyl-7-(4-chloro-phenyl)-5-methyl-heptanoic acid;
(3S,5R)-3-Aminomethyl-7-(3-chloro-phenyl)-5-methyl-heptanoic acid;
(3S,5R)-3-Aminomethyl-7-(2-chloro-phenyl)-5-methyl-heptanoic acid;
(3S,5R)-3-Aminomethyl-7-(4-methoxy-phenyl)-5-methyl-heptanoic acid;
(3S,5R)-3-Aminomethyl-7-(3-methoxy-phenyl)-5-methyl-heptanoic acid;
(3S,5R)-3-Aminomethyl-7-(2-methoxy-phenyl)-5-methyl-heptanoic acid;
(3S,5R)-3-Aminomethyl-7-(4-fluoro-phenyl)-5-methyl-heptanoic acid;
(3S,5R)-3-Aminomethyl-7-(3-fluoro-phenyl)-5-methyl-heptanoic acid;
(3S,5R)-3-Aminomethyl-7-(2-fluoro-phenyl)-5-methyl-heptanoic acid;
(3S,5R)-3-Aminomethyl-5-methyl-oct-7-enoic acid;
(3S,5R)-3-Aminomethyl-5-methyl-non-8-enoic acid;
(E)-(3S,5S)-3-Aminomethyl-5-methyl-oct-6-enoic acid;
(Z)-(3S,5S)-3-Aminomethyl-5-methyl-oct-6-enoic acid;
(Z)-(3S,5S)-3-Aminomethyl-5-methyl-non-6-enoic acid;
(E)-(3S,5S)-3-Aminomethyl-5-methyl-non-6-enoic acid;
(E)-(3S,5R)-3-Aminomethyl-5-methyl-non-7-enoic acid;
(Z)-(3S,5R)-3-Aminomethyl-5-methyl-non-7-enoic acid;
(Z)-(3S,5R)-3-Aminomethyl-5-methyl-dec-7-enoic acid;
(E)-(3S,5R)-3-Aminomethyl-5-methyl-undec-7-enoic acid;
(3S,5S)-3-Aminomethyl-5,6,6-trimethyl-heptanoic acid;
(3S,5S)-3-Aminomethyl-5,6-dimethyl-heptanoic acid;
(3S,5S)-3-Aminomethyl-5-cyclopropyl-hexanoic acid;
(3S,5S)-3-Aminomethyl-5-cyclobutyl-hexanoic acid;
(3S,5S)-3-Aminomethyl-5-cyclopentyl-hexanoic acid; and
(3S,5S)-3-Aminomethyl-5-cyclohexyl-hexanoic acid.
Still another more preferred embodiment of the invention method utilizes a compound of Formula IV selected from:
(3S,5R)-3-Aminomethyl-5-methyl-heptanoic acid;
(3S,5R)-3-Aminomethyl-5-methyl-octanoic acid;
(3S,5R)-3-Aminomethyl-5-methyl-nonanoic acid;
(3S,5R)-3-Aminomethyl-5-methyl-decanoic acid;
(3S,5R)-3-Aminomethyl-5-methyl-undecanoic acid;
(3S,5R)-3-Aminomethyl-5-methyl-dodecanoic acid;
(3S,5R)-3-Aminomethyl-5,9-dimethyl-decanoic acid;
(3S,5R)-3-Aminomethyl-5,7-dimethyl-octanoic acid;
(3S,5R)-3-Aminomethyl-5,8-dimethyl-nonanoic acid;
(3S,5R)-3-Aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid;
(3S,5R)-3-Aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid;
(3S,5R)-3-Aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid;
(3S,5R)-3-Aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid;
(3S,5R)-3-Aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid;
(3S,5R)-3-Aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid;
(3S,5R)-3-Aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid;
(3S,5R)-3-Aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid;
(3S,5R)-3-Aminomethyl-8-cyclopropyl-5-methyl-octanoic acid;
(3S,5R)-3-Aminomethyl-8-cyclobutyl-5-methyl-octanoic acid;
(3S,5R)-3-Aminomethyl-8-cyclopentyl-5-methyl-octanoic acid;
(3S,5R)-3-Aminomethyl-8-cyclohexyl-5-methyl-octanoic acid;
(3S,5S)-3-Aminomethyl-6-fluoro-5-methyl-hexanoic acid;
(3S,5S)-3-Aminomethyl-7-fluoro-5-methyl-heptanoic acid;
(3S,5R)-3-Aminomethyl-8-fluoro-5-methyl-octanoic acid;
(3S,5R)-3-Aminomethyl-9-fluoro-5-methyl-nonanoic acid;
(3S,5S)-3-Aminomethyl-7,7,7-fluoro-5-methyl-heptanoic acid;
(3S,5R)-3-Aminomethyl-8,8,8-fluoro-5-methyl-octanoic acid;
(3S,5R)-3-Aminomethyl-5-methyl-8-phenyl-octanoic acid;
(3S,5S)-3-Aminomethyl-5-methyl-6-phenyl-hexanoic acid; and
(3S,5R)-3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid;
Another preferred embodiment of the invention method utilizes a GABA analog which is a compound of Formulas (1A) or (1B): 
or a pharmaceutically acceptable salt thereof wherein:
n is an integer of from 0 to 2;
R is sulfonamide,
amide,
phosphonic acid,
heterocycle,
sulfonic acid, or
hydroxamic acid;
A is hydrogen or methyl; and 
xe2x80x83straight or branched alkyl of from 1 to 11 carbons, or xe2x80x94(CH2)1-4-Yxe2x80x94(CH2)0-4-phenyl wherein Y is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NRxe2x80x23 wherein:
Rxe2x80x23 is alkyl of from 1 to 6 carbons, cycloalkyl of from 3 to 8 carbons, benzyl or phenyl wherein benzyl or phenyl can be unsubstituted or substituted with from 1 to 3 substituents each independently selected from alkyl, alkoxy, halogen, hydroxy, carboxy, carboalkoxy, trifluoromethyl, and nitro.
A preferred embodiment utilizes a GABA analog which is a compound of Formulas (1A) or (1B), wherein R is a sulfonamide selected from xe2x80x94NHSO2R15 and xe2x80x94SO2NHR15, wherein R15 is straight or branched alkyl or trifluoromethyl.
An especially preferred embodiment utilizes a compound of Formulas (1A) or (1B) selected from:
4-Methyl-2-(1H-tetrazol-5-ylmethyl)-pentylamine;
3-(2-Aminomethyl-4-methyl-pentyl)-4H-[1,2,4]oxadiazole-5-thione, HCl;
(2-Aminomethyl-4-methyl-pentyl)-phosphonic acid;
3-(3-Amino-2-cyclopentyl-propyl)-4H-[1,2,4]oxadiazol-5-one;
3-(3-Amino-2-cyclopentyl-propyl)-4H-[1,2,4]thiadiazol-5-one;
2-Cyclopentyl-3-(2-oxo-2,3-dihydro-2xcex4-[1,2,3,5]oxathiadiazol-4-yl)-propylamine;
3-(3-Amino-2-cyclobutyl-propyl)-4H-[1,2,4]oxadiazol-5-one;
3-(3-Amino-2-cyclobutyl-propyl)-4H-[1,2,4]thiadiazol-5-one; and
2-Cyclobutyl-3-(2-oxo-2,3-dihydro-2xcex4-[1,2,3,5]oxathiadiazol-4-yl)-propylamine.
Another preferred embodiment utilizes a compound of Formulas (1A) or (1B), wherein R is a phosphonic acid, xe2x80x94PO3H2.
Another preferred embodiment utilizes a compound of Formulas (1A) or (1B), wherein R is: 
More preferred is an embodiment that utilizes a compound of Formulas (1A) or (1B), wherein R is: 
Still more preferred is an embodiment that utilizes a compound of Formulas (1A) or (1B) named 3-(2-aminomethyl-4-methyl-pentyl)-4H-[1,3,4]oxadiazol-5-one, or a pharmaceutically acceptable salt thereof.
Still more preferred is an embodiment that utilizes a compound of Formulas (1A) or (1B) named 3-(2-aminomethyl-4-methyl-pentyl)-4H-[1,2,4]oxadiazol-5-one hydrochloride.
Another embodiment of the present invention utilizes a GABA analog that is a compound of Formulas V, VI, VII, or VIII: 
or a pharmaceutically acceptable salt thereof, wherein n is integer of from 1 to 4, where there are stereocenters, each center may be independently R or S.
A preferred embodiment utilizes a compound of Formulas V, VI, VII, or VIII, wherein n is an integer of from 2 to 4.
Another preferred embodiment utilizes a compound of Formula V.
A still more preferred embodiment utilizes a compound of Formulas V, VI, VII, or VIII selected from:
(1xcex1,6xcex1,8xcex2)(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid;
(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid;
(2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid;
(2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid;
(3-Aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid; and;
(3-Aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid.
(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid;
Another still more preferred embodiment utilizes a compound of Formulas V, VI, VII, or VIII selected from:
(1xcex1,5xcex2)(3-Aminomethyl-bicyclo[3.1.0]hex-3-yl)-acetic acid,
(1xcex1,5xcex2)(3-Aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid,
(1xcex1,5xcex2)(2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid,
(1xcex1,6xcex2)(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid,
(1xcex1,7xcex2)(2-Aminomethyl-decahydro-azulen-2-yl)-acetic acid,
(1xcex1,5xcex2)(3-Aminomethyl-bicyclo[3.1.0]hex-3-yl)-acetic acid,
(1xcex1,5xcex2)(3-Aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid,
(1xcex1,5xcex2)(2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid,
(1xcex1,6xcex2)(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid,
(1xcex1,7xcex2)(2-Aminomethyl-decahydro-azulen-2-yl)-acetic acid,
(1xcex1,3xcex1,5xcex1)(3-Aminomethyl-bicyclo[3.1.0]hex-3-yl)-acetic acid,
(1xcex1,3xcex1,5xcex1)(2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid,
(1xcex1,6xcex1,8xcex1)(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid,
(1xcex1,7xcex1,9xcex1)(2-Aminomethyl-decahydro-azulen-2-yl)-acetic acid,
(1xcex1,3xcex2,5xcex1)(3-Aminomethyl-bicyclo[3.1.0]hex-3-yl)-acetic acid,
(1xcex1,3xcex2,5xcex1)(3-Aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid,
(1xcex1,3xcex2,5xcex1)(2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid,
(1xcex1,6xcex1,8xcex2)(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid,
(1xcex1,7xcex1,9xcex2)(2-Aminomethyl-decahydro-azulen-2-yl)-acetic acid,
((1R,3R,6R)-3-Aminomethyl-bicyclo[4.1.0]hept-3-yl)-acetic acid,
((1R,3S,6R)-3-Aminomethyl-bicyclo[4.1.0]hept-3-yl)-acetic acid,
((1S,3S,6S)-3-Aminomethyl-bicyclo[4.1.0]hept-3-yl)-acetic acid,
((1S,3R,6S)-3-Aminomethyl-bicyclo[4.1.0]hept-3-yl)-acetic acid,
((1R,3R,6S)-3-Aminomethyl-bicyclo[4.2.0]oct-3-yl)-acetic acid,
((1R,3S,6S)-3-Aminomethyl-bicyclo[4.2.0]oct-3-yl)-acetic acid,
((1S,3S,6R)-3-Aminomethyl-bicyclo[4.2.0]oct-3-yl)-acetic acid,
((1S,3R,6R)-3-Aminomethyl-bicyclo[4.2.0]oct-3-yl)-acetic acid,
((3xcex1R,5R,7xcex1S)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid,
((3xcex1R,5S,7xcex1S)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid,
((3xcex1S,5S,7xcex1R)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid,
((3xcex1S,5R,7xcex1R)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid,
((2R,4xcex1S,8xcex1R)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid,
((2S,4xcex1S,8xcex1R)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid,
((2S,4xcex1R,8xcex1S)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid,
((2R,4xcex1R,8xcex1S)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid,
((2R,4xcex1S,9xcex1R)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid,
((2S,4xcex1S,9xcex1R)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid,
((2S,4xcex1R,9xcex1S)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid,
((2R,4xcex1R,9xcex1S)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid,
((1R,3R,6S)-3-Aminomethyl-bicyclo[4.1.0]hept-3-yl)-acetic acid,
((1R,3S,6S)-3-Aminomethyl-bicyclo[4.1.0]hept-3-yl)-acetic acid,
((1S,3S,6R)-3-Aminomethyl-bicyclo[4.1.0]hept-3-yl)-acetic acid,
((1S,3R,6R)-3-Aminomethyl-bicyclo[4.1.0]hept-3-yl)-acetic acid,
((1R,3R,6R)-3-Aminomethyl-bicyclo[4.2.0]oct-3-yl)-acetic acid,
((1R,3S,6R)-3-Aminomethyl-bicyclo[4.2.0]oct-3-yl)-acetic acid,
((1S,3S,6S)-3-Aminomethyl-bicyclo[4.2.0]oct-3-yl)-acetic acid,
((1S,3R,6S)-3-Aminomethyl-bicyclo[4.2.0]oct-3-yl)-acetic acid,
((3xcex1R,5R,7xcex1R)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid,
((3xcex1R,5S,7xcex1R)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid,
((3xcex1S,5S,7xcex1S)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid,
((3xcex1S,5R,7xcex1S)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid,
((2R,4xcex1R,8xcex1R)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid,
((2S,4xcex1S,8xcex1R)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid,
((2S,4xcex1R,8xcex1S)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid,
((2R,4xcex1S,8xcex1S)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid,
((2R,4xcex1R,9xcex1R)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid,
((2S,4xcex1R,9xcex1R)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid,
((2S,4xcex1S,9xcex1S)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid, and
((2R,4xcex1S,9xcex1S)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid.
A more preferred embodiment utilizes a compound of Formulas V, VI, VII, or VIII named (1xcex1,3xcex1,5xcex1)(3-aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, or a pharmaceutically acceptable salt thereof.
A still more preferred embodiment utilizes a compound of Formulas V, VI, VII, or VIII named (1xcex1,3xcex1,5xcex1)(3-aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid hydrochloride.
As noted above, the method of this invention utilizes any GABA analog having the characteristic of being an inhibitor of cartilage damage, or a pharmaceutically acceptable salt thereof. For the purposes of the instant invention, a GABA analog having the characteristic of being an inhibitor of cartilage damage is any compound derived from or based upon gamma-aminobutyric acid that provides a cartilage damage inhibiting effect in accordance with this invention.
A compound that is a GABA analog having the characteristic of being an inhibitor of cartilage damage may be readily identified by one of ordinary skill in the pharmaceutical or medical arts by assaying a GABA analog in any number of well known assays for measuring cartilage effects of a compound, and determining the GABA analog""s effects on cartilage damage. These assays include in vitro assays that utilize cartilage samples or in vivo assays in whole animals. In in vitro assays, an amount of a GABA analog or control vehicle may be administered with a cartilage damaging agent to cartilage, and the cartilage damage inhibiting effects in both tests studied by gross examination or histopathologic examination of the cartilage, or by measurement of biological markers of cartilage damage such as, for example, proteoglycan content or hydroxyproline content. In in vivo assays, an amount of a GABA analog or control vehicle may be administered with a cartilage damaging agent to an animal, and the effects of the GABA analog being assayed on cartilage in the animal may be evaluated by gross examination or histopathologic examination of the cartilage, by observation of the effects in an acute model on functional limitations of the affected joint that result from cartilage damage, or by measurement of biological markers of cartilage damage such as, for example, proteoglycan content or hydroxyproline content. Several methods of identifying a GABA analog having the characteristic of being an inhibitor of cartilage damage are described below. The amount to be administered in an assay to identify a GABA analog having the characteristic of being an inhibitor of cartilage damage is dependent upon the particular assay employed, but in any event is not higher than the well known maximum amount of a compound that the particular assay can effectively accommodate.
Any GABA analog having the characteristic of being an inhibitor of cartilage damage is readily available, either commercially, or by synthetic methodology, well-known to those skilled in the art of organic chemistry. A preferred GABA analog to be utilized in the method of this invention is selected from the cyclic amino acids of Formula I. These are described in U.S. Pat. No. 4,024,175 and its divisional U.S. Pat. No. 4,087,544, which are both incorporated herein by reference.
Another preferred method utilizes a GABA analog of Formula II, and these compounds are described in U.S. Pat. No. 5,563,175, which is incorporated herein by reference.
Another preferred method utilizes a GABA analog of Formula III, IIIC, IIIF, IIIG, or IIIH, and these compounds are described in PCT International Application Publication No. WO 99/31075, which is herein incorporated by reference.
Another preferred method utilizes a GABA analog of Formula IV, which are described in PCT International Application Publication No. WO 00/76958, which is herein incorporated by reference.
Other preferred GABA analogs to be utilized in the method of the present invention are compounds of Formulas (1A) and (1B), which are described in PCT International Application Publication No. WO 99/31074, which is herein incorporated by reference.
PCT International Application Publication No. WO 01/28978, which is herein incorporated by reference, describes other preferred GABA analogs to be utilized in the method of the present invention, which are compounds of Formulas V, VI, VII, and VIII.
Other preferred GABA analogs for use in the present invention method are described in PCT International Application No. WO 99/31057, which is herein incorporated by reference. Such GABA analogs are compounds of Formula (1D) and (1E): 
or a pharmaceutically acceptable salt thereof wherein:
n is an integer of from 0 to 2;
R is sulfonamide,
amide,
phosphonic acid,
heterocycle,
sulfonic acid, or
hydroxamic acid; and
X is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or NRxe2x80x21 wherein Rxe2x80x21 is hydrogen, straight or branched alkyl of from 1 to 6 carbons, benzyl, xe2x80x94C(O)Rxe2x80x22 wherein Rxe2x80x22 is straight or branched alkyl of 1 to 6 carbons, benzyl or phenyl or xe2x80x94CO2Rxe2x80x23 wherein Rxe2x80x23 is straight or branched alkyl of from 1 to 6 carbons, or benzyl wherein the benzyl or phenyl groups can be unsubstituted or substituted by from 1 to 3 substituents selected from halogen, trifluoromethyl, and nitro.
Other preferred GABA analogs that may be utilized in the method of the present invention are described in PCT International Application No. WO 98/17627, which is herein incorporated by reference. This embodiment uses a GABA analog that is a compound of formula: 
or a pharmaceutically acceptable salt thereof wherein:
R is hydrogen or lower alkyl;
R1 is hydrogen or lower alkyl; 
xe2x80x83straight or branched alkyl of from 7 to 11 carbon atoms, or xe2x80x94(CH2)(1-4)xe2x80x94Xxe2x80x94(CH2)(0-4)-phenyl wherein
X is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR3- wherein
R3 is alkyl of from 1 to 6 carbons, cycloalkyl of from 3 to 8 carbons, benzyl or phenyl;
wherein phenyl and benzyl can be unsubstituted or substituted with from 1 to 3 substituents each independently selected from alkyl, alkoxy, halogen, hydroxy, carboxy, carboalkoxy, trifluoromethyl, amino, and nitro.
Other preferred GABA analogs that may be utilized in the method of the present invention are described in PCT International Application No. WO 99/61424, which is herein incorporated by reference. This embodiment of the invention method uses a GABA analog that is a compound of formulas (1), (2), (3), (4), (5), (6), (7), or (8): 
or a pharmaceutically acceptable salt thereof or a prodrug thereof wherein:
R1 to R10 are each independently selected from hydrogen or a straight or branched alkyl of from 1 to 6 carbons, benzyl, or phenyl;
m is an integer of from 0 to 3;
n is an integer of from 1 to 2;
o is an integer of from 0 to 3;
p is an integer of from 1 to 2;
q is an integer of from 0 to 2;
r is an integer of from 1 to 2;
s is an integer of from 1 to 3;
t is an integer of from 0 to 2; and
u is an integer of from o to 1.
All U.S. patents and WO publications referenced above are hereby incorporated by reference.
The terms are as defined below or as they otherwise occur in the specification.
As used herein, the phrase xe2x80x9ccartilage damagexe2x80x9d means a disorder of hyaline cartilage and subchondral bone characterized by hypertrophy of tissues in and around the involved joints, which may or may not be accompanied by deterioration of hyaline cartilage surface.
The phrase xe2x80x9chaving the characteristic of being an inhibitor of cartilage damagexe2x80x9d means having the ability to prevent, block, or inhibit damage to cartilage.
It should be appreciated that the terms xe2x80x9cusesxe2x80x9d, xe2x80x9cutilizesxe2x80x9d, and xe2x80x9cemploysxe2x80x9d, and their derivatives thereof, are used interchangeably when describing an embodiment of the present invention.
The phrase xe2x80x9clower alkylxe2x80x9d means a straight or branched alkyl group or radical having from 1 to 6 carbon atoms, and includes methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.
The term xe2x80x9calkylxe2x80x9d is a straight or branched group of from 1 to 8 carbon atoms, unless stated otherwise, including but not limited to methyl, ethyl, propyl, n-propyl, isopropyl, butyl, 2-butyl, tert-butyl, and octyl. Alkyl can be unsubstituted or substituted by hydroxy or from 1 to 3 fluorine atoms. Preferred groups are methyl and ethyl.
The term xe2x80x9calkenylxe2x80x9d is a straight or branched group of from 2 to 8 carbon atoms containing 1 or 2 or 3 double bonds including but not limited to ethenyl, propen-1-yl, propen-2-yl, propen-3-yl, 1-hexen-3-yl, and hept-1,3-dien-7-yl. Alkenyl can be unsubstituted or substituted by from 1 to 3 fluorine atoms.
The term xe2x80x9ccycloalkylxe2x80x9d means a cyclic group of from 3 to 7 carbon atoms including but not limited to cyclopropyl, cyclobutyl, and cycloheptyl.
The benzyl and phenyl groups may be unsubstituted or substituted with from 1 to 3 groups each independently selected from halogen, especially fluoro, alkoxy, alkyl, and NH2.
Halogen includes fluorine, chlorine, bromine, and iodine.
The term xe2x80x9calkoxyxe2x80x9d means the group xe2x80x94O-alkyl wherein alkyl is as defined above.
The terms used to define the invention of compounds of Formulas (1A), (1B), III, IIIC, IIIF, IIIG, and IIIH are as described below.
Sulfonamides are those of formula xe2x80x94NHSO2R15 or xe2x80x94SO2NHR15 wherein R15 is a straight or branched alkyl group of from 1 to 6 carbons or a trifluoromethyl.
Amides are compounds of formula xe2x80x94NHCOR12 wherein R12 is straight or branched alkyl of from 1 to 6 carbons, benzyl, and phenyl.
Phosphonic acids are xe2x80x94PO3H2.
Sulfonic acids are xe2x80x94SO3H. 
Heterocycles are groups of from 1 to 2 rings, with from 1 to 6 heteroatoms selected from oxygen, nitrogen, and sulfur.
Preferred heterocycles are: 
The term alkyl is a straight or branched group of from 1 to 11 carbon atoms including but not limited to methyl, ethyl, propyl, n-propyl, isopropyl, butyl, 2-butyl, tert-butyl, pentyl, hexyl, and n-hexyl, heptyl, octyl, nonyl, decyl, and undecyl except as where otherwise stated.
The cycloalkyl groups are from 3 to 8 carbons and are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl unless otherwise stated.
The benzyl and phenyl groups may be unsubstituted or substituted by from 1 to 3 substituents selected from hydroxy, carboxy, carboalkoxy, halogen, CF3, nitro, alkyl, and alkoxy. Preferred are halogens.
Alkoxy is as defined above for alkyl.
Halogen is fluorine, chlorine, and bromine and preferred are fluorine and chlorine.
Carboalkoxy is xe2x80x94COOalkyl wherein alkyl is as described above. Preferred are carbomethoxy and carboethoxy.
All that is required to practice the method of this invention is to administer a GABA analog having the characteristic of being an inhibitor of cartilage damage, or a pharmaceutically acceptable salt thereof, in an amount that is therapeutically effective to prevent or treat the cartilage damaging condition. Such cartilage damage-inhibiting amount will generally be from about 1 to about 300 mg/kg of subject body weight. Typical doses will be from about 10 to about 5000 mg/day for an adult subject of normal weight. In a clinical setting, regulatory agencies such as, for example, the Food and Drug Administration (xe2x80x9cFDAxe2x80x9d) in the U.S. may require a particular therapeutically effective amount.
In determining what constitutes an effective amount or a therapeutically effective amount of a GABA analog having the characteristic of being an inhibitor of cartilage damage, or a pharmaceutically acceptable salt thereof, for treating or preventing cartilage damage according to the invention method, a number of factors will generally be considered by the medical practitioner or veterinarian in view of the experience of the medical practitioner or veterinarian, published clinical studies, the subject""s (ie, mammal""s) age, sex, weight and general condition, as well as the type and extent of the disease, disorder or condition being treated, and the use of other medications, if any, by the subject. As such, the administered dose may fall within the ranges or concentrations recited above, or may vary outside, ie, either below or above, those ranges depending upon the requirements of the individual subject, the severity of the condition being treated, and the particular therapeutic formulation being employed. Determination of a proper dose for a particular situation is within the skill of the medical or veterinary arts. Generally, treatment may be initiated using smaller dosages of the GABA analog that are less than optimum for a particular subject. Thereafter, the dosage can be increased by small increments until the optimum effect under the circumstance is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.
Pharmaceutical compositions of a GABA analog having the characteristic of being an inhibitor of cartilage damage, or a pharmaceutically acceptable salt thereof, are produced by formulating the active compound in dosage unit form with a pharmaceutical carrier. Some examples of dosage unit forms are tablets, capsules, pills, powders, aqueous and nonaqueous oral solutions and suspensions, and parenteral solutions packaged in containers containing either one or some larger number of dosage units and capable of being subdivided into individual doses.
Some examples of suitable pharmaceutical carriers, including pharmaceutical diluents, are gelatin capsules; sugars such as lactose and sucrose; starches such as corn starch and potato starch; cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, and cellulose acetate phthalate; gelatin; talc; stearic acid; magnesium stearate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and oil of theobroma; propylene glycol, glycerin; sorbitol; polyethylene glycol; water; agar; alginic acid; isotonic saline, and phosphate buffer solutions; as well as other compatible substances normally used in pharmaceutical formulations.
The compositions to be employed in the invention can also contain other components such as coloring agents, flavoring agents, and/or preservatives. These materials, if present, are usually used in relatively small amounts. The compositions can, if desired, also contain other therapeutic agents commonly employed to treat cartilage damage. Further, the compositions can, if desired, also contain other therapeutic agents commonly employed to treat secondary symptoms such as, for example, inflammation or pain that may or may not accompany cartilage damage. For example, the compositions may contain aspirin, naprosyn, or similar anti-inflammatory analgesic agents.
The percentage of the active ingredients in the foregoing compositions can be varied within wide limits, but for practical purposes it is preferably present in a concentration of at least 10% in a solid composition and at least 2% in a primary liquid composition. The most satisfactory compositions are those in which a much higher proportion of the active ingredient is present, for example, up to about 95%.
Preferred routes of administration of a GABA analog having the characteristic of being an inhibitor of cartilage damage, or a pharmaceutically acceptable salt thereof, are oral or parenteral. For example, a useful intravenous dose is between 5 and 50 mg, and a useful oral dosage is between 20 and 800 mg. The dosage is within the dosing range used in treatment of diseases resulting in cartilage damage such as osteoarthritis, or as would be determined by the needs of the patient as described by the physician.
The GABA analog having the characteristic of being an inhibitor of cartilage damage, or a pharmaceutically acceptable salt thereof, may be administered in any form. Preferably, administration is in unit dosage form. A unit dosage form of the GABA analog, or a pharmaceutically acceptable salt thereof, to be used in this invention may also comprise other compounds useful in the therapy of diseases resulting in cartilage damage.
The advantages of using a compound of Formulas I, II, III, IIIC, IIIF, IIIG, IIIH, IV, (1A), (1B), V, VI, VII, or VIII, or a pharmaceutically acceptable salt thereof, including gabapentin, pregabalin, 3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one hydrochloride, 3-(1-aminomethyl-cycloheptylmethyl)-4H-[1,2,4]oxadiazol-5-one hydrochloride, C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, 3-(2-aminomethyl-4-methyl-pentyl)-4H-[1,2,4]oxadiazol-5-one hydrochloride, (1xcex1,3xcex1,5xcex1)(3-aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid hydrochloride, or (3S,5R)-3-aminomethyl-5-methyl-octanoic acid, in the instant invention include the relatively nontoxic nature of the compounds, the ease of preparation, the fact that the compounds are well-tolerated, and the ease of IV and oral administration of the drugs. Further, typically the drugs are not metabolized in the body.
Another important advantage is that the independent anti-inflammatory and pain reducing properties described above for GABA analogs, in combination with the new and unexpected cartilage damage-inhibiting effect of the instant invention, are surprisingly found in one relatively nontoxic agent. The instant invention may, if desired, allow the amount of an anti-inflammatory agent and/or pain relieving agent used in the treatment of patients suffering from cartilage damage and inflammation and/or pain to be reduced or even eliminated. It is known that anti-inflammatory and analgesic agents may produce undesirable side effects such as gastrointestinal bleeding and ulceration. These side effects may be reduced or eliminated by using the instant invention to supplement or substitute treatments using anti-inflammatory and/or analgesic agents.
The invention method is useful in human and veterinary medicines for treating or preventing cartilage damage in a mammal. A mammal includes humans, cats, dogs, horses, cows, pigs, and sheep.
Some of the compounds utilized in a method of the present invention are capable of further forming pharmaceutically acceptable salts, including, but not limited to, acid addition and/or base salts. The acid addition salts are formed from basic compounds, whereas the base addition salts are formed from acidic compounds. All of these forms are within the scope of the compounds useful in the method of the present invention.
Pharmaceutically acceptable acid addition salts of the basic compounds useful in the method of the present invention include nontoxic salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like, as well nontoxic salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge S. M. et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. of Pharma. Sci., 1977;66:1).
An acid addition salt of a basic compound useful in the method of the present invention is prepared by contacting the free base form of the compound with a sufficient amount of a desired acid to produce a nontoxic salt in the conventional manner. The free base form of the compound may be regenerated by contacting the acid addition salt so formed with a base, and isolating the free base form of the compound in the conventional manner. The free base forms of compounds prepared according to a process of the present invention differ from their respective acid addition salt forms somewhat in certain physical properties such as solubility, crystal structure, hygroscopicity, and the like, but otherwise free base forms of the compounds and their respective acid addition salt forms are equivalent for purposes of the present invention.
A pharmaceutically acceptable base addition salt of an acidic compound useful in the method of the present invention may be prepared by contacting the free acid form of the compound with a nontoxic metal cation such as an alkali or alkaline earth metal cation, or an amine, especially an organic amine. Examples of suitable metal cations include sodium cation (Na+), potassium cation (K+), magnesium cation (Mg2+), calcium cation (Ca2+), and the like. Examples of suitable amines are N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge, supra., 1977).
A base addition salt of an acidic compound useful in the method of the present invention may be prepared by contacting the free acid form of the compound with a sufficient amount of a desired base to produce the salt in the conventional manner. The free acid form of the compound may be regenerated by contacting the salt form so formed with an acid, and isolating the free acid of the compound in the conventional manner. The free acid forms of the compounds useful in the method of the present invention differ from their respective salt forms somewhat in certain physical properties such as solubility, crystal structure, hygroscopicity, and the like, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention.
Certain of the compounds useful in the method of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
Certain of the compounds useful in the method of the present invention possess one or more chiral centers, and each center may exist in the R or S configuration. A method of the present invention may utilize any diastereomeric, enantiomeric, or epimeric form of a GABA analog, or a pharmaceutically acceptable salt thereof, as well as mixtures thereof.
Additionally, certain compounds useful in the method of the present invention may exist as geometric isomers such as the entgegen (E) and zusammen (Z) isomers of alkenyl groups. A method of the present invention may utilize any cis, trans, syn, anti, entgegen (E), or zusammen (Z) isomer of a GABA analog, or a pharmaceutically acceptable salt thereof, as well as mixtures thereof.
Certain compounds useful in the method of the present invention can exist as two or more tautomeric forms. Tautomeric forms of the compounds may interchange, for example, via enolization/de-enolization and the like. A method of the present invention may utilize any tautomeric form of a GABA analog, or a pharmaceutically acceptable salt thereof, as well as mixtures thereof.
Intermediates for the synthesis of a GABA analog, or a pharmaceutically acceptable salt thereof, useful in the invention method, and pharmaceutically acceptable salts thereof, may be prepared by one of ordinary skill in the art of organic chemistry by adapting various synthetic procedures that are well-known in the art of organic chemistry. These synthetic procedures may be found in the literature in, for example, Reagents for Organic Synthesis, by Fieser and Fieser, John Wiley and Sons, Inc, New York, 2000; Comprehensive Organic Transformations, by Richard C. Larock, VCH Publishers, Inc, New York, 1989; the series Compendium of Organic Synthetic Methods, 1989,by Wiley-Interscience; the text Advanced Organic Chemistry, 4th edition, by Jerry March, Wiley-Interscience, New York, 1992; or the Handbook of Heterocyclic Chemistry by Alan R. Katritzky, Pergamon Press Ltd, London, 1985, to name a few. Alternatively, a skilled artisan may find methods useful for preparing the intermediates in the chemical literature by searching widely available databases such as, for example, those available from the Chemical Abstracts Service, Columbus, Ohio, or MDL Information Systems GmbH (formerly Beilstein Information Systems GmbH), Frankfurt, Germany.
Preparations of the compounds useful in a method of the present invention may use starting materials, reagents, solvents, and catalysts that may be purchased from commercial sources or they may be readily prepared by adapting procedures in the references or resources cited above. Commercial sources of starting materials, reagents, solvents, and catalysts useful in preparing invention compounds include, for example, The Aldrich Chemical Company, and other subsidiaries of Sigma-Aldrich Corporation, St. Louis, Mo., BACHEM, BACHEM A. G., Switzerland, or Lancaster Synthesis Ltd, United Kingdom.
Syntheses of some compounds useful in the method of the present invention may utilize starting materials, intermediates, or reaction products that contain a reactive functional group. During chemical reactions, a reactive functional group may be protected using protecting groups that render the reactive group substantially inert to the reaction conditions employed. A protecting group is introduced onto a starting material prior to carrying out the reaction step for which a protecting group is needed. Once the protecting group is no longer needed, the protecting group can be removed. It is well within the ordinary skill in the art to introduce protecting groups during a synthesis of a GABA analog, or a pharmaceutically acceptable salt thereof, and then later remove them. Procedures for introducing and removing protecting groups are known and referenced such as, for example, in Protective Groups in Organic Synthesis, 2nd ed., Greene T. W. and Wuts P. G., John Wiley and Sons, New York: N.Y., 1991, which is hereby incorporated by reference. Thus, for example, protecting groups such as the following may be utilized to protect amino, hydroxyl, and other groups: carboxylic acyl groups such as, for example, formyl, acetyl, and trifluoroacetyl; alkoxycarbonyl groups such as, for example, ethoxycarbonyl, tert-butoxycarbonyl (BOC), xcex2,xcex2,xcex2-trichloroethoxycarbonyl (TCEC), and xcex2-iodoethoxycarbonyl; aralkyloxycarbonyl groups such as, for example, benzyloxycarbonyl (CBZ), para-methoxybenzyloxycarbonyl, and 9-fluorenylmethyloxycarbonyl (FMOC); trialkylsilyl groups such as, for example, trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBDMS); and other groups such as, for example, triphenylmethyl (trityl), tetrahydropyranyl, vinyloxycarbonyl, ortho-nitrophenylsulfenyl, diphenylphosphinyl, para-toluenesulfonyl (Ts), mesyl, trifluoromethanesulfonyl, and benzyl. Examples of procedures for removal of protecting groups include hydrogenolysis of CBZ groups using, for example, hydrogen gas at 50 psi in the presence of a hydrogenation catalyst such as 10% palladium on carbon, acidolysis of BOC groups using, for example, hydrogen chloride in dichloromethane, trifluoroacetic acid (TFA) in dichloromethane, and the like, reaction of silyl groups with fluoride ions, and reductive cleavage of TCEC groups with zinc metal.
Preparations of a GABA analog, or a pharmaceutically acceptable salt thereof, useful in the method of the present invention are incorporated by reference to the patents or patent application publications described above, or are illustrated in the Schemes below.
Compounds of Formulas III, IIIC, IIIF, IIIG, and IIIH may be prepared according to the following methods. Sulfonamides can be synthesized by the general route outlined in Scheme 1. 
(i) Diethylcyanomethyl phosphonate, NaH, tetrahydrofuran;
(ii) Nitromethane, tetrabutylammonium fluoride, tetrahydrofuran;
(iii) Borane methyl sulphide, toluene;
(iv) Triethylamine, R15SO2Cl, tetrahydrofuran;
(v) 10% Pdxe2x80x94C, hydrogen gas, methanol.
Tetrazoles can be synthesized by the general route outlined in Scheme 2. 
(i) Trimethylsilylazide, Trimethylaluminium (2M in hexanes), toluene;
(ii) Raney Nickel, Methanol.
Amides can be synthesized by the general route outlined in Scheme 3. 
(i) Diethylcyanomethyl phosphonate, NaH, tetrahydrofuran;
(ii) Nitromethane, tetrabutylammonium fluoride, tetrahydrofuran;
(iii) Borane methyl sulphide, toluene;
(iv) Triethylamine, R15COCl, tetrahydrofuran;
(v) 10% Pdxe2x80x94C, hydrogen gas, methanol.
Heterocycles such as 
can be synthesized by the general route outlined in Scheme 4. 
(i) NH2OH.HCl, Et3N;
(ii) iBuOCOCl, pyridine followed by reflux in xylene;
(iii) Fe/HCl.
Compound 1 [(1-nitromethyl-cyclohexyl)acetonitrile] can be treated with hydroxylamine hydrochloride in the presence of a base such as triethylamine to give compound 2.
The heterocyclic compound 3 can be prepared from compound 2 by treatment with iso-butyl chloroformate in the presence of a base such as pyridine followed by reflux in a solvent such as xylene. The nitro compound (compound 3) can be converted to the required amine by reduction, for example, with iron and hydrochloric acid.
Heterocycles such as: 
can be synthesized by the general route outlined in Scheme 5a. 
Heterocycles such as: 
can be synthesized by the general route outlined in Scheme 5b. 
Heterocycles such as: 
can be synthesized by the general route shown in Scheme 6 below: 
(i) NH2OH.HCl, Et3N;
(ii) 1,1xe2x80x2-thiocarbonyldiimidazole followed by DBU or DBN;
(iii) Fe/HCl.
Compound 1 [(nitromethyl-cyclohexyl)acetonitrile] can be treated with hydroxylamine hydrochloride in the presence of a base such as triethylamine to give compound 2.
The heterocyclic compound 3 can be prepared from compound 2 by treatment with 1,1xe2x80x2-thiocarbonyldiimidazole followed by a base such as 1,8-diazabicyclo-[4,5,0]-undec-7-ene (DBU) or 1,5-diazabicyclo[2.2.2]octane] (DBN).
The nitro compound (compound 3) can be converted to the required amine by reduction, for example, with iron and hydrochloric acid. Heterocycles such as: 
can be syntesized following the general route as shown in Scheme 7. 
(i) NH2OH.HCl, Et3N;
(ii) 1,1xe2x80x2-thiocarbonyldiimidazole followed by silica gel or BF3.OEt2;
(iii) Fe/HCl.
Compound 1 [(nitromethyl-cyclohexyl)acetonitrile] can be treated with hydroxylamine hydrochloride in the presence of a base such as triethylamine to give compound 2.
The heterocyclic compound 3 can be prepared from compound 2 by treatment with 1,1xe2x80x2-thiocarbonyldiimidazole followed by treatment with silica gel or boron trifluoride etherate.
The nitro compound (compound 3) can be converted to the required amine by reduction, for example, with iron and hydrochloric acid.
Heterocycles such as: 
can be synthesized following the general route outlined in Scheme 8: 
(i) NH2OH.HCl, Et3N;
(ii) Pyridine, SOCl2;
(iii) Fe/HCl.
Compound 1 [(nitromethyl-cyclohexyl)acetonitrile] can be treated with hydroxylamine hydrochloride in the presence of a base such as triethylamine to give compound 2.
The heterocyclic compound 3 can be prepared from compound 2 by treatment with thionyl chloride in the presence of a base such as pyridine.
The nitro compound (compound 3) can be converted to the required amine by reduction, for example, with iron and hydrochloric acid.
The following examples are illustrative of the preparation of compounds of Formulas III, IIIC, IIIF, IIIG, or IIIH; they are not intended to limit the scope.